Methods for treating spastic
conditions



United States Patent 3,326,129 METHUDS F03 TREATING SPATIC CQNDHTIGNS Charles Gansser, Paris, France, and Walter Schindler, Riehen, near Easel, Switzerland, assignors to Gezgy Chemical tiergroration, Ardsley, N.Y., a corporation of New York No Drawing. Original application Oct. 39, 1962, Ser. No. 235,177. Divided and this application Feb. 10, 1964, Ser. No. 355,136

Claims priority, application Switzerland, Aug. 28, 1959, 77,491/59; Jan. 13, Hat 299/60; Feb. 25, 1960, 2,108/60 3 Qlaims. (Cl. 161-65) This application is a division of Ser. No. 235,177, filed Oct. 30, 1962, and now abandoned, which case is a continuation-in-part of Ser. No. 52,044, filed Aug. 26, 1960.

The present invention concerns new N-heterocyclic compounds having valuable pharmacological properties.

It is increasingly evident that in higher forms of life, especially in mammals, a large number of concurrent biological processes of great varietyoften interrelated and/ or interdependent-are constantly at work, the optimal integrated dynamic balance of which is known as health of mind and body. It is, therefore clear that disturbance of one or more of the component factors entering into this dynamic balance, which is health, will lead to imbalance, i.e. to ill health either of the body, or of the mind, or both.

In view of the plurality and complexity of these dynamic interrelations and interdependencies, it is of importance to the medical art to have at its disposal a choice among a variety of medicinal agents. Thus, compounds principally exerting a single, specific major pharmacodynamic effect are not the only ones desirable. Equally desirable are compounds which inherently exert a combination of several major pharmacodynamic effects. Moreover, the demands to be made on a pharmaceutical agent are further complicated by the fact that the first type of compounds, namely those with a single major effect, as well as those which exert a spectrum of diverse effects, may be desired for application either in the mental domain, or in the somatic domain, or in both domains simultaneously.

It is known that compounds of the general formulae and X Y (w CH2([)HOH2N\ CH3 R wherein R is lower alkyl X and Y are either hydrogen, or taken together, an additional bond, and

m is zero or one,

are primarily distinguished by sizeable reserpine-antagonistic activity and, therefore valuable in the treatment of "ice mental disorders, particularly depressions. Apart from this principal antidepressive component, these compounds, moreover, exhibit in varying degree antihistaminic, antiemetic, sedative and anticonvulsant properties in their pharmacodynamic spectrum.

We have now surprisingly found that compounds of the formulae III om,

C H2 CH: O HN CH3 C 2H: and

CHzCHzCH-Am wherein Am is dialkylamino, the alkyl radicals of which have each from one to four carbon atoms, and Am is preferably dimethylamino or diethyl-amino, are, contrary to what would have been expected, clearly distinguished from the above mentioned prior art compounds, useful in the management of mental illness, by a different pharmacodynamic spectrum which is useful preponderantly in the somatic domain: Compounds of Formulae I and II exhibt as outstanding spasmolytic components in their spectrum of activity a strong anticholinergic and a strong musculotropic efiect on smooth muscle, and further a secondary antihistaminic effect. In contrast to the prior art compounds, the reserpine-antagonistic activity of the compounds according to the Formulas I and II is reduced to such an extent as to render them particularly useful by virtue of the combination of the above mentioned spasmolytic components with a reduced reserpine-antagonistic activity for the treatment of somatic conditions such as those of the gastro-intestinal, urogenital and biliary tracts, and of the bronchial system. Since the treatment of such afflictions is often adversely affected by central nervous stimulation (of which reserpine-antagonism is one indicator) the reduction and, in certain cases, elimination of the central stimulant component with concomittant increase in the anticholinergic and musculotropic activities as achieved in the compounds of the instant invention, is particularly advantageous and completely unexpected.

It has also been found that the compounds of the formulae exhibit spasmolytic, pre'ponderantly anticholinergic activity, the musculotropic component being relatively weaker, although still about 7 to 8 times as strong as papaverine. Moreover, the compound of Formula III is devoid of reserpine-antagonistic activity.

It is pertinent to note, moreover, that substitution of the benzene ring of the compounds of the invention, e.g. with chlorine, adversely affects the spasmolytic qualities of these compounds.

Moreover, it has been found that the compound of the formula N OH:

| CHz-C HnCH-N CH3 CH3 (IA) CH=OH and the compounds of the above defined general Formula II can be produced by reacting iminodibenzyl of the formula CHr-CH:

respectively in the presence of an acid binding agent with a reactive ester of a basic alcohol of the general formula CH: (VII) wherein Am has the meaning given above for Am or is pyrrolidinyl-(l).

Particularly suitable condensing agents are sodium amide, lithium amide, potassium amide, sodium or potassium, butyl lithium, phenyl lithium, sodium hydride or lithium hydride. The reaction can be performed in the presence or absence of an inert organic solvent, of which examples are benzene, toluene and Xylene.

As reactive esters of basic alcohols of the above general Formula VII, in particular the halides, aryl sulphonic acid esters and methane sulfonic acid esters are used. Examples thereof are 'y-dimethylamino-n-butyl chloride, 'y-methylethylamino-n-butyl chloride, 'y-diethyl- .arnino-n-butyl chloride, 'y-di-n-butylamino-n-butyl chloride, 'y-pyrrolidino-n-butyl chloride and the corresponding bromides and 'y-toluene sulfonic acid esters. These reactive esters of basic alcohols are obtained, for example, starting from 1,3- butylene glycol by reacting it with acetyl chloride to form 3-chloro-n-butyl acetate, reacting the latter with a suitable secondary amine and converting the 3-tertiary amino-n-butanol obtained into its chloride, bromide or toluene sulfonic acid ester.

The compounds of the general Formulae I, II, III and IV form salts, some of which are water-soluble with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane disulfonic acid, acetic acid, citric acid, malic acid, succinic acid, maleic aid, fumaric acid, tartaric acid, benzoic acid, phthalic acid and 8-chlorotheophyllin.

The following non-limitative examples further illustrate the production of the new compounds according to the invention. Where not otherwise stated, parts are given as parts by weight and their relationship to parts by volume is as that of grams to cubic centimeters. The temperatures are in degrees centigrade.

Example I 18.3 parts of iminostilbene are dissolved in 490 parts of anhydrous benzene and 18.6 parts of 'y-diethylarninon-butyl chloride in parts by volume of anhydrous benzene are added.

A suspension of 4 parts of sodium amide in toluene is added dropwise at 55 while stirring well and the whole is then refluxed for 15 hours. Water is then added to the reaction mixture and the basic portions are removed from the benzene phase by extracting three times with diluted hydrochloric acid. The combined extracts are made alkaline and ethered out, and the ethereal solution is dried over potassium carbonate and concentrated. The residue is distilled in a high vacuum whereupon the 5-('y-diethylamino-n-butyl)-iminostilbene passes over at 185-190 and 0.5 mm. pressure.

The hydrochloride prepared with alcoholic hydrochloric acid melts at 193-195" (from acetone).

On using -pyrrolidinyl-n-butyl chloride (B.P. 82 87 S-(y-pyrrolidinyl n butyl)-iminostilbene B.P. 206208), and on using 'y-dimethylamino-n-butyl chloride, 5 ('y dimethylamino n butyl) iminostilbene (B.P. 172176) are obtained in an analogous manner.

Example 2 9.7 parts of iminodibenzyl are dissolved in 50 parts by volume of anhydrous benzene. A suspension of 2.2 parts of sodium amide in toluene is added dropwise at 60 while stirring strongly whereupon the sodium compound of the iminodibenzyl precipitates.

The benzene solution of the base from 10.3 parts of 'y-dimethylamino-n-butyl chloride-hydrochloride (MP. 182) in 150 parts by volume of anhydrous benzene is added dropwise while stirring strongly at 60 and the reaction mixture is kept for 2 hours at this temperature. The whole is then refluxed for 12 hours. Water is then added to the reaction mixture and the basic portions are removed from the benzene phase by extracting three times with dilute hydrochloric acid. The combined extracts are made alkaline and ethered out, the ethereal solution is dried over potassium carbonate and concentrated. The residue is distilled in a high vacuum whereupon the 5- (y-dimethylamino-n-butyl)-iminodibenzyl passes over at under 0.02 mm. pressure.

The hydrochloride prepared with alcoholic hydrochloric acid melts at 146-l48 (from acetone).

On using 'y-diethylamino-n-butyl chloride (B.P. 63), 5 ('y dimethylamino-n-butyl)-iminodibenzyl (B.P. 196-200) is obtained in an analogous manner. Its hydrochloride prepared with alcoholic hydrochloric acid melts at 165166.

On using 'y-pyrrolidyl-n-butyl chloride, 5-( -pyrrolidyln-butyl)-iminodibenzyl is obtained in an analogous manner.

Example 3 9.7 parts of iminodibenzyl are dissolved in 50 parts by volume of anhydrous toluene. A suspension of 2.3 parts of sodium amide in toluene is added dropwise at 60 while stirring well whereupon the sodium compound of the iminodibenzyl precipitates.

The toluene solution of the base from 10.4 parts of 'y-methyl-ethylamino-n-butyl chloride-hydrochloride in 75 parts by volume of anhydrous toluene is added dropwise at 60 while stirring strongly and the reaction mixture is kept at this temperature for 2 /2 hours, after which it is refluxed for 15 hours. Water is then added to the reaction mixture and the basic portions are removed from the toluene phase by extracting three times with dilute hydrochloric acid. The combined extracts are made alkaline and ethered out, the ethereal solution is dried over potassium carbonate and concentrated. The residue is distilled in a high vacuum whereupon S-(y-methylethylamino-n-butyl)iminodibenzyl is obtained.

To produce dosage units for peroral application, the active above-mentioned compounds or the salts thereof are combined, e.g., with solid, pulverulent carriers such as talcum, lactose, saccharose, sorbitol, mannite; starches such as potato starch, corn starch or amylopectin; cellulose derivatives or gelatine, possibly with the addition of lubricants such as magnesium or calcium stearate or polyethylene oxides of suitable molecular weights (Carbo- Wax) and disintegrating agents such as, e.g., alginfc acid, laminaria powder or citrus pulp powder, to form tablets or drage cores. The latter are coated, for example, with concentrated sugar solutions which can contain for example, shellack, gum arabic, talcum and/or titanium doxide, or with Carbowax with the addition of talcum or titanium dioxide. Dyestuffs are added to the drages, e.g., to distinguish between the ditferent dosages. Soft gelatine capsules (pearl-shaped closed capsules) and other closed capsules consist, for example, of ge-latine and contain, e.g., mixtures of the active ingredient or a suitable salt with Carbowax, and hard gelatine capsules contain, e.g., granulates of the active substance or of a suitable salt with gelatine, magnesium stearate or stearic acid. Suppositories are an example of dosage units for rectal application. They consist of a combination of the active substance or of a suitable salt with a neutral fatty base.

Ampoules for parenteral, particularly intramuscular application preferably contain a water soluble salt of the active substance according to the invention and suitable stabilizing agents and, optionally, buffer substances in aqueous solution. Antioxidizin agents such as sodium bisulphite, sodium sulphite, ascorbic acid or rongalite (formaldehyde-sodium bisulphite compound) are suitable in particular as stabilizing agents either alone or coinbined, in total concentrations between about 0.1-0.5 per mille. Because of its ability to form chelates, ascorbic acid has an additional stabilizing effect; in this function it can also be replaced by other chelate-formers. The best stability of the active ingredient is attained if the pH of the ampoule solutions is between 3.5 and 5. This range can be attained, e.g., by mixtures in suitable ratio of sodium sulphite, sodium bisulp-hite and/or ascorbic acid, or by the addition of other buffer substances such as citric acid and/or salts thereof. In addition, the ampoules can contain a slight amount of a usual conserving agent.

The following examples illustrate the production of two typical forms of application for oral and one for parenteral use, but the invention is in no way limited thereto.

Example 4 250 g. of 5-('ydimethylamino-n-butyl)-iminodibenzyl hydrochloride are mixed with 175.80 g. of lactose and 169.70 parts of potato starch, the mixture is moistened with an alcoholic solution of g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicium dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing 100 mg. and containing 25 mg. of active substance (hydrochloride). The tablets can be marked with break lines if desired to enable a closer adaption of the dosage to be made.

6 Example 5 A granulate is prepared from 250 g. of S-(diethylamino-n-butyl)-iminostilbene hydrochloride. 175.90 g. of lactose and the alcoholic solution of 10 g. of stearic acid After drying, the granulate is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate and pressed into 10,000 drage centres. These are then coated with a concentrated syrup of 502.28 g. of crystallised saccharose, 6 g. of shellack, 10 g. of gum arabic, 0.22 g. of dyestutf and 1.5 g. of titanium dioxide and dried. The drages obtained each weigh 120 mg. and contain 25 mg. of active substance.

Example 6 1.25 g. of 5-('y-dimethylamino-n-butyl)-iminostilbene hydrochloride, 0.10 g. of ascorbic acid, 0.05 g. of sodium bisulphite and 0.10 g. of sodium sulphite are dissolved in distilled water until the volume is ml. This solution is used to fill amporules, each of preferably 2 ml. and containing 25 mg. of active substance. The ampoules are heat-sterilized in the usual Way.

The active substance used in the above examples can be replaced, e.g., by the same amounts of S-(y-diethylarnino-n-butyl)-iminodibenzyl hydrochloride or of a salt of one of the other bases embraced by the general Formula II with another of the acids given above.

In order to illustrate the advantageous spectrum of pharmacological properties of the new azepine derivatives according to the invention, pharmacological tests were carried out with (I) 5-('y-dimethylamino-n-butyl)-iminodibenzyl, (II) 5 ('y-diethylamino-n-butyl) -irninodibenzyl,

( III) 5 'y-dimethylamino-n-butyl -iminostilbene, (IV) 5- ('y-diethylamino-n-butyl) -iminostilbene,

on the one hand, and with the following most closely related, homologous compounds among which there are well-known commercial anti-depressive agents on the other hand.

(V) 5- ('y-dimethylamino-n-propyl) -iminodibenzyl,

(VI) 5- 6-dimethylarnino-n-butyl -iminodibenzyl,

(VII 5- y-dimethylamino-fl-methyhpropyl) -iminodibenzyl,

(VIII) 5-('y-dimethylamino-n-propyl)-iminostilbene,

(IX) 5- 6-dimethylamino-n-butyl -iminostilbene,

(X) 5-('y-dimethylamino-B-methyl-propyl)-iminostilbene.

The results of these tests carried out with the abovelisted Compounds I to X as well as with (XI) 5-('y-pyrrolidinyl-n-butyl)-iminodibenzyl, are given in Tables I and II below.

(A) T oxz'city (B) Spasmolytic activity Surviving guinea pig ileum (according to Magnus, cf. Pil igers Archiv fiir die gesarnete Physiologi, 102, 123 (1904)) in tyrode solution, was caused to contract by means of standard doses of (a) acetylcholine chloride,

(b) histamine hydrochloride, and (c) barium chloride Equipotent lytic doses of test compound and of (a) atropin,

(b) N-benzyl-N',N' -dimethyl- N phenylethylenediamine (Angtergan), and

(c) papaverine were ascertained, and the results expressed as weight units of test compound equivalent to one weight unit of (a) atropin,

(b) Antergan, and

(c) papaverine Atropin equivalents were determined on rabbit (R), as well as on guinea pig (GP) ileum.

The resulting values are given in Table I below, under the sub-headings of (a) anticholinergic (b) antihistaminic, and

(c) musculotropic activity respectively.

(C) Reserpine antagonism (Ptosis test) Male white rats weighing from about 120 to 150 grams were each injected subcutaneously, first with 50 mg. per kg. of body weight of test substance, and, 24 hours later, with reserpine in amounts of 2 mg. per kg. of body weight. Control animals were injected subcutaneously with reserpine alone.

The action of the test compounds against the reserpineinduced closure of the eyelids was measured by visually determining the aperture of the eyelids, i.e. the distance between the upper and the lower eyelids, for a period of three hours, said observation period running from the third to the sixth hour after the administration of reserpine. The observations were made at 30 minute intervals during the three-hour period. This resulted in seven values which were averaged.

The difference between the aperture of the eyelids of the control animals on the one hand, and the animals previously injected with the test compound, on the other hand, was calculated and expressed as percent of change from the control value, negative values indicating reserpine antagonism; -100% thus indicates normal, open eyes.

TABLE 1 Compounds Prior Art Compounds according to the invention Tests V VI VII I II Toxicity: LD 50 35 45 88 33 21 Spasrnolytic Activity (21) Anti-cholinergic:

40 22 II 24 40 25 1.1 4. 5 6 5. 9 5. 5 (e) O. 3 0.018 0. 23 Roserpine-autiagonism 87 10 50 33 29 TABLE II Prior Art Compounds accord- Compouuds ing to the invention Test VIII IX X IV III XI Toxicity: LD 50 41 35 19 25 15 Spasmolytic Activity:

(a) Auti-eholiuergio:

(R). 55 5.3 4. 2 (GP) 7.9 14 70 2. 7 3.1 1.1 (b) Anti-histaminic. 5. 9 5. 5 10 4. 5 (e) Musculotropic 0.2 0.16 0.016 0. 016 0.135 Reserpine-antagonism 74 72 29 67 i0 What we claim is:

1. A method for the treatment of spastic afflictions of the gastro-intestinal, urogenital and biliary tracts and of the bronchial system in mammals, which comprises administering to a mammal suffering from such afiiiction an effective amount of a compound of the formula thereby having a spasmolytic effect on said affliction, with predominant anticholinergic action and musculotropic action on the smooth muscle, and secondary antihistaminic action and reduced reserpine-antagonistic activity.

2. A method for the treatment of spastic afiiictions of the gastro-intestinal, urogenital and biliary tracts and of the bronchial system in mammals, which comprises administering to a mammal suffering from such afiiiction an effective amount of a compound of the formula wherein Am is a member selected from the group consisting of dialkylamino with each alkyl having maximally 4 carbon atoms, and pyrrolidinyl-(l), thereby having a spasmolytic eifect on said afiiiction, with predominant anticholinergic action and musculotropic action on the smooth muscle, and secondary antihistaminic action and reduced reserpine-antagonistic activity.

3. A method according to claim 2, wherein the compound corresponds to the formula whereby substantially no reserpine-antagonistic activity is exerted.

References Cited by the Examiner UNITED STATES PATENTS 3,074,931 1/1963 Craig 260239 ALBERT T. MEYERS, Primary Examiner.

JULIAN S. LEV-ITT, Examiner.

S. J. FRIEDMAN, M. I. COHEN, Assistant Examiners. 

1. A METHOD FOR THE TREATMENT OF SPASTIC AFFLICATIONS OF THE GASTRO-INTESTINAL, UROGENITAL AND BILIARY TRACTS AND OF THE BRONCHIAL SYSTEM IN MAMMALS, WHICH COMPRISES ADMINISTERING TO A MAMMAL SUFFERING FROM SUCH AFFLICTION AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA 